Malonyl-coenzyme A (malonyl-CoA), generated by acetyl-CoA carboxylases ACC1 and ACC2, is a key metabolite in the regulation of energy homeostasis. Here, we show that Acc2-/- mutant mice have a normal life span, a higher fatty acid oxidation rate, and lower amounts of fat. In comparison to the wild type, Acc2-deficient mice had 10- and 30-fold lower levels of malonyl-CoA in heart and muscle, respectively. The fatty acid oxidation rate in the soleus muscle of the Acc2-/- mice was 30% higher than that of wild-type mice and was not affected by addition of insulin; however, addition of insulin to the wild-type muscle reduced fatty acid oxidation by 45%. The mutant mice accumulated 50% less fat in their adipose tissue than did wild-type mice. These results raise the possibility that pharmacological manipulation of ACC2 may lead to loss of body fat in the context of normal caloric intake.

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Fatty acids are a major energy source and important constituents of membrane lipids, and they serve as cellular signaling molecules that play an important role in the etiology of the metabolic syndrome. Acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and the regulator of fatty acid oxidation. They are highly regulated and play important roles in the energy metabolism of fatty acids in animals, including humans. They are presently considered as an attractive target to regulate the human diseases of obesity, diabetes, cancer, and cardiovascular complications. In this review we discuss the role of fatty acid metabolism and its key players, ACC1 and ACC2, in animal evolution and physiology, as related to health and disease.-Wakil, S. J., and L. A. Abu-Elheiga. Fatty acid metabolism: target for metabolic syndrome. J. Lipid Res. 2009. 50: S138-S143.Supplementary key words acetyl-coenzyme A carboxylases 1 and 2 • ACC1 and ACC2 • fatty acid synthaseLong-chain fatty acids are major sources of energy and important components of the lipids that comprise the cellular membrane. They are either derived from food or are synthesized from acetyl-coenzyme A (acetyl-CoA) through complex sets of reactions; that includes glycolysis and the citric acid cycle, which collectively lead to the formation of the backbone carbons of fatty acids and glycerols for the synthesis of lipids (1). Acetyl-CoA is also a product of the b-oxidation of fatty acids. Hence, acetyl-CoA stands out as the key intermediate in carbohydrate, amino acid, and lipid metabolism. The synthesis of fatty acids by fatty acid synthase (FAS) requires acetyl-CoA, malonyl-CoA, and NADPH. Malonyl-CoA is the C 2 donor in the de novo synthesis of fatty acids, and it plays an important role as an inhibitor of the carnitine/palmitoyl shuttle system for fatty acid oxidation (2). To facilitate these two different roles, fatty acid synthesis and oxidation, two distinct enzymes have evolved: acetyl-CoA carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2). ACC1, with its biotin prosthetic group, was first discovered in our laboratory in 1958 (3). In prokaryotes, ACC1 is composed of three distinct proteins: biotin carboxylase, biotin carboxyl carrier protein, and transcarboxylase. In the presence of ATP, biotin carboxylase transfers CO 2 from bicarbonate to the biotin carboxyl carrier protein, forming the carboxybiotin derivative. The transcarboxylase catalyzes the transfer of the carboxyl group to acetyl-CoA, forming malonyl-CoA. In eukaryotes, however, these proteins are contained within a single multifunctional protein (Mr 262,000) that is encoded by a single gene. While ACC1 is generally expressed in all tissues, it is expressed more in lipogenic tissues: liver, adipose, and lactating mammary gland. In contrast, ACC2 (Mr 282,000) is highly expressed in heart and muscle and to a lesser extent in liver (4). ACC1 and ACC2 are encoded by separate genes localized at chromosomes 17q12 and 12q23,...

Animals, including humans, express two isoforms of acetyl-CoA carboxylase (EC 6.4.1.2), ACC1 (Mr ‫؍‬ 265 kDa) and ACC2 (Mr ‫؍‬ 280 kDa). The predicted amino acid sequence of ACC2 contains an additional 136 aa relative to ACC1, 114 of which constitute the unique N-terminal sequence of ACC2. The hydropathic profiles of the two ACC isoforms generally are comparable, except for the unique N-terminal sequence in ACC2. The sequence of amino acid residues 1-20 of ACC2 is highly hydrophobic, suggesting that it is a leader sequence that targets ACC2 for insertion into membranes. The subcellular localization of ACC2 in mammalian cells was determined by performing immunofluorescence microscopic analysis using affinity-purified anti-ACC2-specific antibodies and transient expression of the green fluorescent protein fused to the C terminus of the N-terminal sequences of ACC1 and ACC2. These analyses demonstrated that ACC1 is a cytosolic protein and that ACC2 was associated with the mitochondria, a finding that was confirmed further by the immunocolocalization of a known human mitochondria-specific protein and the carnitine palmitoyltransferase 1. Based on analyses of the fusion proteins of ACC-green fluorescent protein, we concluded that the N-terminal sequences of ACC2 are responsible for mitochondrial targeting of ACC2. The association of ACC2 with the mitochondria is consistent with the hypothesis that ACC2 is involved in the regulation of mitochondrial fatty acid oxidation through the inhibition of carnitine palmitoyltransferase 1 by its product malonyl-CoA.A cetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate substrate that plays a pivotal role in the regulation of fatty acid metabolism. Besides its role in the biosynthesis of long-chain fatty acids (1-3), malonyl-CoA has been implicated in the regulation of the carnitine palmitoyl-CoA shuttle system that is involved in the mitochondrial ␤-oxidation of long-chain fatty acids. In animals, two isoforms of the carboxylase have been identified, ACC1 (M r ϭ 265,000) and ACC2 (M r ϭ 280,000) (4, 5). The two enzymes are encoded by separate genes and display distinct tissue distribution and regulation (6-9). The ACC1 carboxylases are highly expressed in lipogenic tissues, such as liver and adipose, and their levels are regulated transcriptionally while their activities are regulated posttranslationally by phosphorylation͞dephosphorylation of selected serine residues and by allosteric regulation through the action of citrate and palmitoyl-CoA (10-18). Dietary and hormonal states of the animal affect the level and activities of the ACC1 enzymes. A carbohydrate-rich, low-fat diet stimulates the expression and activities of ACC1, whereas starvation and diabetes reduce the ACC1 activities by repressing the expression of the ACC1 gene or by increasing the phosphorylation levels of the ACC1 protein (or both). Treating diabetic animals with insulin increases the activity of the enzyme either by dephosphorylation of the protein or by...